Cell injury by Hetu (Msc. Medical Biochemistry)

   CELL INJURY

 

 Cell injury is defined as the effect of a variety of stresses due to etiologic agents a cell encounters, resulting in changes in its internal and external environment. The cellular response to stress may vary and depends upon following two variables:-

1. Host factors i.e. the type of cell and tissue involved.
2. Factors pertaining to injurious agent i.e. extent and type of cell injury. Various forms of cellular responses to cell injury may be as follows:- 

•  When there is increased functional demand, the cell may adapt to the changes which are expressed morphologically, which then revert back to normal after the stress is removed (cellular adaptations).
• When the stress is mild to moderate, the injured cell may recover (reversible cell injury), while persistent and severe form of cell injury may cause cell death (irreversible cell injury).

3. The residual effects of reversible cell injury may persist in the cell as evidence of cell injury at subcellular level (subcellular changes), or metabolites may accumulate within the cell (intracellular accumulations).

ETIOLOGY OF CELL INJURY:-

The cells may be broadly injured by two major ways: 

A. Genetic causes 

B. Acquired causes 

The acquired causes of disease comprise vast majority of common diseases afflicting mankind. Based on underlying agent, the acquired causes of cell injury can be further categorised as under: 

1. Hypoxia and ischaemia. 

2. Physical agent. 

3. Chemical agents and drugs. 

4. Microbial agent.

5. Immunologic agents. 

6. Nutritional derangements. 

7. Ageing.

8. Psychogenic diseases. 

9. Iatrogenic factors. 

10. Idiopathic diseases.

PATHOGENESIS OF CELL INJURY:-

The underlying alterations in biochemical systems of cells for reversible and irreversible cell injury by various agents are complex and varied. However, in general, irrespective of the type, following common scheme applies to most forms of cell injury by various agents.

1.Factors pertaining to etiological agent and host (A)Type duration and severity of injurious agents; (B) Type, status and adaptability of target cell.

2.Common underlying mechanisms Irrespective of other factors, following essential intracellular biochemical phenomena underlie all forms of cell injury: (A) Mitochondrial damage causing ATP depletion. (B) Cell membrane damage disturbing the metabolic and trans-membrane exchanges. (C) Release of toxic free radicals. 

3. Usual morphologic changes The morphologic changes of rever - sible cell injury (e.g. hydropic swelling) appear earlier while later morphologic alterations of cell death are seen (e.g. in myocardial infarction).

4. Functional implications and disease outcome Eventually, cell injury affects cellular function adversely which has bearing on the body. Consequently, clinical features in the form of symptoms and signs would appear. 

PATHOGENESIS OF ISCHAEMIC AND HYPOXIC INJURY 

Ischaemia and hypoxia are the most common forms of cell injury. Although underlying intracellular mechanisms and ultrastructural changes seen in reversible and irreversible cell injury by hypoxia-ischaemia (depending upon extent of hypoxia and type of cells involved) are a continuation of the process, these mechanisms are discussed separately below.

REVERSIBLE CELL INJURY :- If the ischaemia or hypoxia is of short duration, the effects may be reversible on rapid restoration of circulation e.g. in coronary artery occlusion, myocardial contractility, metabolism and ultrastructure are reversed if the circulation is quickly restored. The sequential biochemical and ultrastructural changes in reversible cell injury are as under. 

1. Decreased generation of cellular ATP: Damage by ischaemia from interruption versus hypoxia from other causes All living cells require continuous supply of oxygen to produce ATP which is essentially required for a variety of cellular functions (e.g. membrane transport, protein synthesis, lipid synthesis and phospholipid metabolism). ATP in human cell is derived from 2 sources: 

” Firstly, by aerobic respiration or oxidative phosphorylation (which requires oxygen) in the mitochondria.

 ” Secondly, cells may subsequently switch over to anaerobic glycolytic oxidation to maintain constant supply of ATP (in which ATP is generated from glucose/glycogen in the absence of oxygen).

Ischaemia due to interruption in blood supply as well as hypoxia from other causes limit the supply of oxygen to the cells, thus causing decreased ATP generation from ADP:

” In ischaemia from interruption of blood supply, aerobic respiration as well as glucose availability are both compromised resulting in more severe and faster effects of cell injury. Ischaemic cell injury also causes accumulation of metabolic waste products in the cells.

” On the other hand, in hypoxia from other causes (RBC disorders, heart disease, lung disease), anaerobic glycolytic ATP generation continues, and thus cell injury is less severe.

 However, highly specialised cells such as myocardium, proximal tubular cells of the kidney, and neurons of the CNS are dependent solely on aerobic respiration for ATP generation and thus these tissues suffer from ill-effects of ischaemia more severely and rapidly.

 

2. Intracellular lactic acidosis: Nuclear clumping Due to low oxygen supply to the cell, aerobic respiration by mitochondria fails first. This is followed by switch to anaerobic glycolytic pathway for the requirement of energy (i.e. ATP). This results in rapid depletion of glycogen and accumulation of lactic acid lowering the intracellular pH.

3. Damage to plasma membrane pumps: Hydropic swelling and other membrane changes Lack of ATP interferes in generation of phospholipids from the cellular fatty acids which are required for continuous repair of membranes. This results in damage to membrane pumps operating for regulation of sodium-potassium and calcium.

4. Reduced protein synthesis: Dispersed ribosomes As a result of continued hypoxia, membranes of endoplasmic reticulum and Golgi apparatus swell up. Ribosomes are detached from granular (rough) endoplasmic reticulum and polysomes are degraded to monosomes, thus dispersing ribosomes in the cytoplasm and inactivating their function. Similar reduced protein synthesis occurs in Golgi apparatus.

Ultrastructural evidence of reversible cell membrane damage is seen in the form of loss of microvilli, intramembranous particles and focal projections of the cytoplasm (blebs). Myelin figures may be seen lying in the cytoplasm or present outside the cell. 

Up to this point, withdrawal of acute stress that resulted in reversible cell injury can restore the cell to normal state.

IRREVERSIBLE CELL INJURY :- Persistence of ischaemia or hypoxia results in irreversible damage to the structure and function of the cell (cell death). Two essential phenomena always distinguish irreversible from rever - sible cell injury .

” Inability of the cell to reverse mitochondrial dysfunction on reperfusion or reoxygenation. ” Disturbance in cell membrane function in general, and in plasma membrane in particular.

In addition, there is further reduction in ATP, continued depletion of proteins, reduced intracellular pH, and leakage of lysosomal enzymes into the plasma. These biochemical changes have effects on the ultrastructural components of the cell. 

1. Calcium influx: Mitochondrial damage As a result of continued hypoxia , a large cytosolic influx of calcium ions occurs, especially after reperfusion of irreversibly injured cell.

2. Activated phospholipases: Membrane damage Damage to membrane function in general, and plasma membrane in particular, is the most important event in irreversible cell injury. Increased cytosolic influx of calcium in the call activates endogenous phospholipases. These , in turn, degrade membrane phospholipids progressively which are the main  constituents of the lipid bilayer membrane.

3. Intracellur proteases: cytoskeletan damage the normal cytoskeleton of the cell (microfilaments , microtubules and intermediate filaments) which anchors the cell membrane is damaged due to degradation by activated intracellular proteases or by physical effect of cell swelling producing irreversible cell membrane injury.

4. Activated endonucleases: Nuclear damage DNA or nucleoproteins are damaged by the activated lysosomal enzymes such as proteases and endonucleases. Irreversible damage to the nucleus can be in three forms: i) Pyknosis: Condensation and clumping ii) Karyorrhexis: Fragmentation iii) Karyolysis: Dissolution.

5. Lysosomal hydrolytic enzymes: Lysosomal damage, cell death and phagocytosis The lysosomal membranes are damaged and result in escape of lysosomal hydrolytic enzymes. The dead cell is eventually rep - laced by masses of phospholipids called myelin figures which are either phagocytosed by macrophages or there may be formation of calcium soaps.  

Liberated enzymes leak across the abnormally permeable cell membrane into the serum, the estimation of which may be used as clinical parameters of cell death.